ABSTRACT This is the first resubmission of a methodology oriented R01 grant application. The public health burden of Alzheimer's disease (AD) is increasing with devastating projections on an international basis. Although much knowledge has been gained recently about the AD disease process, as a result of amyloid-? (A?) positron- emission tomography (PET) imaging in combination with MRI hippocampal volume, FDG PET, amyloid and tau cerebrospinal fluid concentrations and cognitive performance - there is still much to be understood, particularly as the field moves further from end-stage disease to preclinical AD. A decade ago, AD clinical research was transformed when it became possible to specifically detect in vivo one of the defining pathologic changes of AD, A? plaques using PET. However, amyloid deposition is not itself robustly associated with clinical status, cognitive performance, or stage of progression. In contrast, the pattern of tau pathology, the other AD-defining lesion, is more closely related to the AD phenotype than A? pathology. A first generation tau-PET radiotracer, [18F]T807 (a.k.a. [18F]AV-1451; Flortaucipir), emerged as a promising tool for human tau imaging and is the most widely used to date, with pioneering studies originating from our laboratories at the Massachusetts General Hospital. There remains a critical need to improve tau-PET tracers in 3 areas in order to improve early disease detection and enable multiple longitudinal follow-ups required for disease-modifying therapeutic trials: 1) reduction of off-target binding in, for example, structures adjacent to hippocampus; 2) improved in vivo kinetics to ensure stable quantification of tau load across low-to-high binders; and 3) greater signal-to-noise at the pre-symptomatic end of the AD spectrum. We have recently co-developed a novel second generation tau- PET tracer, [18F]MK-6240, in collaboration with Merck Research Laboratories. The overall goal is to comprehensively evaluate [18F]MK-6240, using a longitudinal study design to show improved quantification of tau load throughout brain. Our study will address remaining key obstacles needed to ensure successful application of [18F]MK-6240 for clinical research investigations of AD. Specifically our aims are: A) To perform a fully quantitative arterial-based kinetic evaluation of [18F]MK-6240 kinetics; B) To measure the distribution of [18F]MK-6240 in brain, at baseline and at 1-year (yr) follow-up; C) To develop a high yield radiosynthesis of [18F]MK-6240 using our advanced radiofluorination technology thereby facilitating widespread distribution and multi-center trials; and D) and exploratory aim to examine region- and substrate-specific autoradiographic binding of [18F]MK-6240 and its off-target binding to other amyloid and non-amyloid proteins. The rigorous evaluation of this novel, highly specific tau-PET tracer with greater sensitivity for in vivo measurement of tau pathology and monitoring of disease staging is critically needed. This new radiopharmaceutical is envisioned to enable smaller sample sizes, shorter proof-of-mechanism timelines, and facilitate optimal patient selection for AD treatment development.